Abstract Candida albicans is a commensal fungus residing in the oral cavity, the gastrointestinal tract, and the vagina of humans and other warm-blooded animals. It is also an opportunistic pathogen with a disease spectrum ranging from mild superficial infections in overall healthy people to wide-spread, and life-threatening systemic infections in patients with compromised immunity due to underlying disease or immunosuppressive therapy. C. albicans is the 4th most common microorganism causing nosocomial blood stream infections, therefore representing a serious public health challenge of increasing medical and socioeconomic importance. While an impaired host immune function clearly contributes to the severity of Candida infections, the fungus must possess characteristics that facilitate the transition from a harmless commensal to an aggressive pathogen. During the course of infection, C. albicans encounters many different host environments to which it must adapt rapidly to ensure growth and survival. Furthermore, it must be able to cope with alterations in established niches during long-term persistence in the host. Our long-term goal is to determine exactly how the transition from commensal to pathogen takes place and how it can be prevented. Our working hypothesis is that the adaptation of C. albicans through genetic and phenotypic changes during infection plays a much greater role in host-pathogen interactions than is currently appreciated. We are just beginning to understand how C. albicans adapts to varying host environments, whether adaptation is triggered by the host, and how the fungus modulates antigenicity through variations in its surface proteins. One of the major virulence factors in C. albicans is its ability to switch between yeast and hyphal growth morphologies. Yeast and hyphal forms vary in cell wall composition, which leads to differential recognition by the innate immune system and affects the outcome of infection. Here, we will identify the underlying genetic basis for alterations in the morphological program acquired during early stages of infection, and we will determine how specific mutations directly affect host-pathogen interactions, including host recognition, host response, and virulence. We will study strains with abnormal filamentation phenotypes recovered from an oropharyngeal candidiasis and a blood stream infection model and will address the following questions: 1) What are the genomic changes that underlie the morphologically diverse mutants? 2) How fit are these mutants under physiologically relevant growth and stress conditions? 3) Which genetic factors contribute to the unification of cellular morphology, morphology of the multicellular community (colony) and the cell wall? and 4) How does the host recognize and respond to the repertoire of morphologies it encounters? These studies will advance our understanding of host-pathogen interactions from the pathogen perspective that will help reveal how the host and the fungus maintain their balanced relationship in healthy individuals and how disruption of this interaction causes devastating infections in the immunocompromised host.